US4153728A - Phenoxyalkylcarboxylic acid compounds and therapeutic compositions - Google Patents
Phenoxyalkylcarboxylic acid compounds and therapeutic compositions Download PDFInfo
- Publication number
- US4153728A US4153728A US05/733,542 US73354276A US4153728A US 4153728 A US4153728 A US 4153728A US 73354276 A US73354276 A US 73354276A US 4153728 A US4153728 A US 4153728A
- Authority
- US
- United States
- Prior art keywords
- ethyl
- phenoxy
- tert
- butyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 57
- 239000002253 acid Substances 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 title claims description 18
- 230000001225 therapeutic effect Effects 0.000 title claims description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 210000002966 serum Anatomy 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 150000002632 lipids Chemical class 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 5
- 238000004220 aggregation Methods 0.000 claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 claims abstract description 4
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims abstract description 4
- 241000124008 Mammalia Species 0.000 claims abstract 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- 230000002776 aggregation Effects 0.000 claims description 3
- 210000001772 blood platelet Anatomy 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 101150108015 STR6 gene Proteins 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ATDWJOOPFDQZNK-UHFFFAOYSA-N N-acetyltyramine Chemical compound CC(=O)NCCC1=CC=C(O)C=C1 ATDWJOOPFDQZNK-UHFFFAOYSA-N 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 7
- -1 methylene, methylmethylene, dimethylmethylene Chemical group 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000155 melt Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- WPMYUUITDBHVQZ-UHFFFAOYSA-N 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoic acid Chemical compound CC(C)(C)C1=CC(CCC(O)=O)=CC(C(C)(C)C)=C1O WPMYUUITDBHVQZ-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DZGWFCGJZKJUFP-UHFFFAOYSA-N Tyramine Natural products NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- XZZWSUAELSBSNA-UHFFFAOYSA-N ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(CCN)C=C1 XZZWSUAELSBSNA-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 229960003732 tyramine Drugs 0.000 description 3
- DZGWFCGJZKJUFP-UHFFFAOYSA-O tyraminium Chemical compound [NH3+]CCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-O 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- ULPGOEGOTZCCPK-UHFFFAOYSA-N ethyl 2-[4-(2-acetamidoethyl)phenoxy]-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(CCNC(C)=O)C=C1 ULPGOEGOTZCCPK-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- ZSVFZXMDSIAKNR-UHFFFAOYSA-N n-acetyl-n-[2-(4-hydroxyphenyl)ethyl]acetamide Chemical compound CC(=O)N(C(C)=O)CCC1=CC=C(O)C=C1 ZSVFZXMDSIAKNR-UHFFFAOYSA-N 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- OJKKTILHACTYMS-UHFFFAOYSA-N (2-hydrazinylidenehydrazinyl)-oxido-oxophosphanium Chemical class NN=NN[P+](=O)[O-] OJKKTILHACTYMS-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 description 1
- RYEJORVMPOOLGZ-UHFFFAOYSA-N 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=C(CCN)C=C1 RYEJORVMPOOLGZ-UHFFFAOYSA-N 0.000 description 1
- DGPWASIVWNADCJ-UHFFFAOYSA-N 2-[4-(2-azaniumylethyl)phenoxy]acetate Chemical compound NCCC1=CC=C(OCC(O)=O)C=C1 DGPWASIVWNADCJ-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- YEXOWHQZWLCHHD-UHFFFAOYSA-N 3,5-ditert-butyl-4-hydroxybenzoic acid Chemical compound CC(C)(C)C1=CC(C(O)=O)=CC(C(C)(C)C)=C1O YEXOWHQZWLCHHD-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
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- 229930195725 Mannitol Natural products 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
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- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
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- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
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- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- ZHPJLBQLCHSICY-UHFFFAOYSA-N methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate Chemical compound COC(=O)C(C)(C)OC1=CC=C(CCN)C=C1 ZHPJLBQLCHSICY-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention is concerned with new phenoxyalkylcarboxylic acid compounds and to therapeutic compositions and methods containing and utilizing such compounds.
- the new phenoxyalkylcarboxylic acid derivatives of the present invention are of the formula: ##STR2## wherein
- B is a valency bond or a straight-chained or branched, saturated or unsaturated hydrocarbon radical containing up to 3 carbon atoms,
- R 1 , R 2 and R 3 which can be the same or different, are hydrogen atoms or lower alkyl; and the pharmacologically compatible salts thereof.
- Examples of straight-chained or branched, saturated or unsaturated hydrocarbon radicals containing up to 3 carbon atoms which are represented by B include alkylene, such as methylene, methylmethylene, dimethylmethylene and ethylene; and alkenylene, such as vinylene.
- the lower alkyl radicals R 1 , R 2 and R 3 can be straight chained or branched and contain up to 6 and preferably up to 3 carbon atoms.
- the new compounds according to the present invention show, in animal experiments, a considerable lowering of the serum lipid level and of the cholesterol level, without undesirable side effects.
- the new compounds according to the present invention and the salts thereof are, therefore, effective agents for the treatment of atherosclerosis. Furthermore, they possess an outstanding thrombocyte aggregation-inhibiting action. In addition, they can be used for the inhibition of the growth of tumors and retard the ageing of cells. Furthermore, they are also valuable intermediates for the preparation of antibiotics with a ⁇ -lactam structure.
- the new compounds according to the present invention can be prepared by reacting an aminophenol of the general formula: ##STR3## in which n has the same meaning as above, optionally with the intermediate protection of the amino or hydroxyl group, in any order with an acid of the general formula: ##STR4## in which B has the same meaning as above, or with a derivative thereof, and with a compound of the general formula: ##STR5## in which R 1 and R 2 have the same meanings as above, X is a reactive group and Y is a --COOR 3 group, in which R 3 has the same meaning as above or Y is a residue which, after condensation has taken place, is converted into a --COOR 3 group, whereafter, if desired, the substituent R 3 in the product obtained is, after the condensation, converted in known manner into another substituent R 3 and the compound obtained is, if desired, converted into a pharmacologically compatible salt.
- the process according to the present invention is preferably carried out in two stages.
- the condensation of the compounds of general formula (II) with derivatives of the carboxylic acids (III), on the one hand, and with compounds of the general formula (IV), on the other hand, is preferably carried out in such a manner that, first, one of the two reactive groups of the compounds (II) is blocked by a protective group which is easily split off, the compound obtained is reacted with a derivative of a carboxylic acid (III) or with a compound of general formula (IV), the protective group is again removed and subsequently this reactive intermediate is reacted with the hitherto unused compound of general formula (IV) or (III).
- the reactive derivatives of the carboxylic acids (III) are preferably the halides, anhydrides, the mixed carboxylic acid-carbonic acid anhydrides or the imidazolides. These can be reacted, for example, under the conditions of a Schotten-Baumann reaction, i.e. with the addition of a tertiary amine, such as pyridine, dimethylaniline or triethylamine, with the compound (II) in an inert solvent, for example, tetrahydrofuran, dioxan or an excess of the tertiary amine.
- a Schotten-Baumann reaction i.e. with the addition of a tertiary amine, such as pyridine, dimethylaniline or triethylamine
- an inert solvent for example, tetrahydrofuran, dioxan or an excess of the tertiary amine.
- a previous blocking of the phenolic hydroxyl group by esterification is
- a reactive derivative of a compound (II) can be reacted with a carboxylic acid of general formula (III).
- Reactive derivatives of compounds (II) include, for example, the phosphoazoamides, which are formed in situ when a phosphorus trihalide, such as phosphorus trichloride, is added to a solution of the compound (II) protected on the hydroxyl group.
- a phosphorus trihalide such as phosphorus trichloride
- acid acceptor there can be used a tertiary amine, for example pyridine. If this reaction is carried out in the presence of a carboxylic acid, then the desired amides with a protected hydroxyl function are obtained directly.
- the amino group of the compound (II) into a protected group, for example a phthalimide group, which, after the reaction, can easily be split off again, for example by reaction with hydroxylamine.
- a protected group for example a phthalimide group
- other groups known from peptide chemistry for the protection of the amine group which, after the reaction, are split off again.
- the amino group is preferably blocked with an acyl group, such as a formyl or acetyl group, which, after the reaction, can easily be split off again with a strong base, for example sodium hydroxide or potassium hydroxide.
- reactive compounds (IV) those are especially preferred in which X is a radical derived from an anion of a strong acid, for example of a hydrohalic or sulphonic acid.
- the reaction can also be promoted by converting the phenolic hydroxyl group of the compound (II) into a phenolate, for example, by reaction with a sodium alcoholate.
- the reaction of the two components is carried out in a solvent, for example, toluene, a xylene, methyl ethyl ketone or dimethyl formamide, preferably at an elevated temperature.
- substituents Y in compounds of general formula (IV) which can be converted into a --COOR 3 group include the nitrile, carbaldehyde and hydroxymethyl groups.
- the saponification is advantageously carried out with a strong base, such as sodium or potassium hydroxide, in a mixture of methanol and water, at ambient temperature or at a moderately elevated temperature.
- a carboxylic acid can also be esterified in the usual manner or an ester with a particular radical R 3 can be converted into one with a different radical R 3 by transesterification.
- esterification of the carboxylic acids is preferably carried out in the presence of an acid catalyst, for example hydrochloric acid, sulphuric acid or p-toluenesulphonic acid, or a strongly acidic ion exchange resin.
- an acid catalyst for example hydrochloric acid, sulphuric acid or p-toluenesulphonic acid, or a strongly acidic ion exchange resin.
- Transesterifications require the addition of a small amount of a basic substance, for example of an alkali metal or alkaline earth metal hydroxide or of an alkali metal alcoholate.
- carboxylic acids for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine
- carboxylic acids can be reacted with the appropriate bases.
- Mixtures of carboxylic acids with an appropriate alkali metal carbonate or bicarbonate can also be used.
- a mixture of 44.8 g. (0.25 mol) N-acetyl-tyramine, 69.5 g. (0.5 mol) anhydrous, powdered potassium carbonate and 750 ml. anhydrous butan-2-one is heated for 2 hours, while stirring at reflux temperature, and then 73.2 g. (0.375 mol) ethyl ⁇ -bromoisobutyrate and 1 g. potassium iodide are added thereto and the reaction mixture is again heated at reflux temperature.
- reaction mixture is heated for 30 minutes on a steambath, cooled and poured into ice-water.
- the mixture is acidified with concentrated hydrochloric acid and the precipitated material is taken up in ethyl acetate.
- the ethyl acetate phase is washed 3 times with 0.5N aqueous sodium hydroxide solution, once with 0.5N hydrochloric acid and then with water, thereafter dried and finally evaporated.
- the evaporation residue is recrystallized from an ethyl acetate-ligroin mixture to give 10.2 g.
- the N-acetyl-tyramine used as starting material can be prepared by one of the two following methods:
- the above-mentioned acid can also be prepared by the hydrolysis of the methyl ester which melts at 105°- 107° C., after recrystallization from ethyl acetate-ligroin.
- the methyl ester can be prepared, in a manner analogous to that described in Example 1, by the condensation of 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid with methyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate in the presence of phosphorus trichloride.
- test compounds were administered orally to male rats of a weight of about 200 g (10 animals per substance in each case) in the dosages listed below.
- the treatment continued for 7 days. On the seventh day the animals were killed by neck blow and bled white.
- the concentration of the triglycerides and the cholesterol in the serum of the animals was then determined enzymatically.
- the control animals were given carrier substances without test compound. The results, expressed as percent reduction as compared to the control animals, are set forth in the following Table:
- arachidonic acid was administered intravenously to male rabbits in a dosage of 1.4 mg/kg.
- One group of 5 rabbits was used as a control group and a second group was used as the test group.
- Two hours before injection of the arachidonic acid the test group was pre-treated with 2- ⁇ 4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy ⁇ -2-methylpropionic acid in dosages of 10 mg/kg and 20 mg/kg.
- novel compounds may be administered by themselves or in conjunction with carriers which are pharmacologically acceptable, either active or inert.
- the dosage units are similar to those of the heretofore known anti-cholesterol agents, e.g., about 1 to 2 grams per day for an adult or about 30 mg/kg per day although higher or lower dosages can be used.
- the compounds are administered in the course of a day, i.e., about four applications of 500 mg. each at spaced time intervals or 8 of about 250 mg. each.
- a convenient form of administration is in a gelatin capsule.
- the new compounds according to the present invention are mixed in the usual manner with appropriate pharmaceutical diluents or carriers, arome, flavoring and coloring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example olive oil.
- the new compounds according to the present invention can be administered orally or parenterally in admixture with solid or liquid pharmaceutical diluents or carriers.
- injection medium it is preferred to use water which contains the stabilizing agents, solubilizing agents and/or buffers conventionally used in injection solutions.
- Additives of this kind include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex-forming agents (such as ethylenediamine-tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbitan anhydrides.
- Solid carrier materials include, for example, starch, lactose, mannitol, methyl, cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
- Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening agents.
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Novel phenoxyalkylcarboxylic acid compounds of the formula ##STR1## wherein B is a valency bond or a straight-chained or branched, saturated or unsaturated hydrocarbon radical containing up to 3 carbon atoms;
N is 1 or 2 and
R1, r2 and R3 are hydrogen or lower alkyl; and the pharmacologically compatible salts thereof; have been found to be outstandingly effective in lowering the serum lipid level and the cholesterol level in mammals without inducing undesired side effects and to possess excellent thrombocyte-aggregation inhibiting activity.
Description
The present invention is concerned with new phenoxyalkylcarboxylic acid compounds and to therapeutic compositions and methods containing and utilizing such compounds.
The new phenoxyalkylcarboxylic acid derivatives of the present invention are of the formula: ##STR2## wherein
B is a valency bond or a straight-chained or branched, saturated or unsaturated hydrocarbon radical containing up to 3 carbon atoms,
N IS 1 OR 2 AND
R1, R2 and R3, which can be the same or different, are hydrogen atoms or lower alkyl; and the pharmacologically compatible salts thereof.
Examples of straight-chained or branched, saturated or unsaturated hydrocarbon radicals containing up to 3 carbon atoms which are represented by B include alkylene, such as methylene, methylmethylene, dimethylmethylene and ethylene; and alkenylene, such as vinylene.
The lower alkyl radicals R1, R2 and R3 can be straight chained or branched and contain up to 6 and preferably up to 3 carbon atoms.
The above-given definitions of the compounds according to the present invention are also to include all possible stereoisomers, as well as mixtures thereof.
The new compounds according to the present invention, as well as their pharmacologically compatible salts, show, in animal experiments, a considerable lowering of the serum lipid level and of the cholesterol level, without undesirable side effects. The new compounds according to the present invention and the salts thereof are, therefore, effective agents for the treatment of atherosclerosis. Furthermore, they possess an outstanding thrombocyte aggregation-inhibiting action. In addition, they can be used for the inhibition of the growth of tumors and retard the ageing of cells. Furthermore, they are also valuable intermediates for the preparation of antibiotics with a β-lactam structure.
The new compounds according to the present invention can be prepared by reacting an aminophenol of the general formula: ##STR3## in which n has the same meaning as above, optionally with the intermediate protection of the amino or hydroxyl group, in any order with an acid of the general formula: ##STR4## in which B has the same meaning as above, or with a derivative thereof, and with a compound of the general formula: ##STR5## in which R1 and R2 have the same meanings as above, X is a reactive group and Y is a --COOR3 group, in which R3 has the same meaning as above or Y is a residue which, after condensation has taken place, is converted into a --COOR3 group, whereafter, if desired, the substituent R3 in the product obtained is, after the condensation, converted in known manner into another substituent R3 and the compound obtained is, if desired, converted into a pharmacologically compatible salt.
The process according to the present invention is preferably carried out in two stages. The condensation of the compounds of general formula (II) with derivatives of the carboxylic acids (III), on the one hand, and with compounds of the general formula (IV), on the other hand, is preferably carried out in such a manner that, first, one of the two reactive groups of the compounds (II) is blocked by a protective group which is easily split off, the compound obtained is reacted with a derivative of a carboxylic acid (III) or with a compound of general formula (IV), the protective group is again removed and subsequently this reactive intermediate is reacted with the hitherto unused compound of general formula (IV) or (III).
The reactive derivatives of the carboxylic acids (III) are preferably the halides, anhydrides, the mixed carboxylic acid-carbonic acid anhydrides or the imidazolides. These can be reacted, for example, under the conditions of a Schotten-Baumann reaction, i.e. with the addition of a tertiary amine, such as pyridine, dimethylaniline or triethylamine, with the compound (II) in an inert solvent, for example, tetrahydrofuran, dioxan or an excess of the tertiary amine. A previous blocking of the phenolic hydroxyl group by esterification is preferred but etherification with a compound of general formula (IV) is especially preferred. On the other hand, a reactive derivative of a compound (II) can be reacted with a carboxylic acid of general formula (III). Reactive derivatives of compounds (II) include, for example, the phosphoazoamides, which are formed in situ when a phosphorus trihalide, such as phosphorus trichloride, is added to a solution of the compound (II) protected on the hydroxyl group. As solvent and simultaneously as acid acceptor, there can be used a tertiary amine, for example pyridine. If this reaction is carried out in the presence of a carboxylic acid, then the desired amides with a protected hydroxyl function are obtained directly.
For the reaction of the compound (II) with a compound (IV), it has proved to be advantageous first to convert the amino group of the compound (II) into a protected group, for example a phthalimide group, which, after the reaction, can easily be split off again, for example by reaction with hydroxylamine. However, there can also be introduced other groups known from peptide chemistry for the protection of the amine group which, after the reaction, are split off again. The amino group is preferably blocked with an acyl group, such as a formyl or acetyl group, which, after the reaction, can easily be split off again with a strong base, for example sodium hydroxide or potassium hydroxide.
As reactive compounds (IV), those are especially preferred in which X is a radical derived from an anion of a strong acid, for example of a hydrohalic or sulphonic acid. The reaction can also be promoted by converting the phenolic hydroxyl group of the compound (II) into a phenolate, for example, by reaction with a sodium alcoholate. The reaction of the two components is carried out in a solvent, for example, toluene, a xylene, methyl ethyl ketone or dimethyl formamide, preferably at an elevated temperature.
Examples of substituents Y in compounds of general formula (IV) which can be converted into a --COOR3 group include the nitrile, carbaldehyde and hydroxymethyl groups.
A conversion of a substituent R3 possibly to be carried out subsequently to the condensation can take place, for example, by saponification of a carboxylic acid ester (R3 = alkyl) with a mineral acid or an alkali metal hydroxide in a polar solvent, for example water, methanol, ethanol, dioxan or acetone. The saponification is advantageously carried out with a strong base, such as sodium or potassium hydroxide, in a mixture of methanol and water, at ambient temperature or at a moderately elevated temperature. On the other hand, however, a carboxylic acid can also be esterified in the usual manner or an ester with a particular radical R3 can be converted into one with a different radical R3 by transesterification. The esterification of the carboxylic acids is preferably carried out in the presence of an acid catalyst, for example hydrochloric acid, sulphuric acid or p-toluenesulphonic acid, or a strongly acidic ion exchange resin. Transesterifications, on the other hand, require the addition of a small amount of a basic substance, for example of an alkali metal or alkaline earth metal hydroxide or of an alkali metal alcoholate.
For the preparation of salts with pharmacologically compatible organic or inorganic bases, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids (I; R3 = H) can be reacted with the appropriate bases. Mixtures of carboxylic acids with an appropriate alkali metal carbonate or bicarbonate can also be used.
The following Examples are given for the purpose of illustrating the present invention:
A mixture of 44.8 g. (0.25 mol) N-acetyl-tyramine, 69.5 g. (0.5 mol) anhydrous, powdered potassium carbonate and 750 ml. anhydrous butan-2-one is heated for 2 hours, while stirring at reflux temperature, and then 73.2 g. (0.375 mol) ethyl α-bromoisobutyrate and 1 g. potassium iodide are added thereto and the reaction mixture is again heated at reflux temperature.
After 40 hours and again after 70 hours boiling, in each case there are additionally added 35 g. potassium carbonate and 36.6 g. ethyl α-bromoisobutyrate. After a total reaction period of 130 hours, the reaction mixture is evaporated in a vacuum, poured into ice water and extracted with diethyl ether. The ethereal extract is washed 3 times with 0.5N aqueous sodium hydroxide solution, then with water and finally dried over anhydrous calcium chloride and evaporated. There are obtained 83.8 g. of an oily residue which still contains ethyl α-bromoisobutyrate. The oil is kept for 5 hours at 70° C. under a pressure of 0.1 mm. Hg and then cooled. The resultant crystalline slurry is washed with ligroin and dried. There are obtained 69.8 g. (95% of theory) of still not quite pure ethyl 2-[4-(2-acetaminoethyl)-phenoxy]-2-methylpropionate; m.p. 48°- 51° C.
A solution of 119.1 g. (0.407 mol) ethyl 2-[4-(2-acetaminoethyl)-phenoxy]-2-methylpropionate in 750 ml. ethanol is mixed with a solution of 224.4 g. (4.00 mol) potassium hydroxide in 800 ml. water and heated under reflux for 8 hours. After cooling, exactly 4.00 mol hydrogen chloride, for example in the form of 2N hydrochloric acid, are added thereto, the mixture is more strongly cooled and, after some time, the precipitated crystals are filtered off with suction. These are washed with water and dried. There are obtained 48.4 g. (53% of theory) of product; m.p. 274° C. (decomp.). From the mother liquor, there are obtained, after distilling off the ethanol and cooling, a further 32.5 g. (36% of theory) of product; m.p. 263°- 270° C. The crude 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionic acid thus obtained is recrystallized from ethanol-water (4:1 v/v) and then has a melting point of 284° C. The corresponding hydrochloride has a melting point of 187°- 189° C.
A solution of58 g.(0.26 mol) of this carboxylic acid in 600 ml. absolute ethanol is gasified with dry hydrogen chloride, while stirring and cooling with ice, from the surface until saturated. The reaction mixture is left to stand in a closed vessel for 12 hours. Subsequently, the ethanol and hydrogen chloride are removed in a vacuum. Water is added to the residue, followed by extracting 3 times with diethyl ether. The aqueous phase is rendered distinctly alkaline and then extracted 3 times with chloroform. The chloroform extract is washed with a little water, dried over anhydrous potassium carbonate and evaporated. By distillation of the residue, there are obtained, between 125 and 128° C./0.1 mm.Hg, 53.2 g. (82% of theory) colorless ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate.
To a solution of 8.83 g. (35.2 mMol) ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate in 75 ml. anhydrous pyridine is added dropwise at 5° C. 1.54 ml. (17.6 mMol) phosphorus trichloride. The reaction mixture is stirred for 30 minutes at 5° C., then 8.8 g. (35.2 mMol) 3,5-di-tert.-butyl-4-hydroxybenzoic acid introduced, followed by further stirring for 1 hour at 5° C., whereafter the reaction mixture is left to stand overnight at ambient temperature. Subsequently, the reaction mixture is heated for 30 minutes on a steambath, cooled and poured into ice-water. The mixture is acidified with concentrated hydrochloric acid and the precipitated material is taken up in ethyl acetate. The ethyl acetate phase is washed 3 times with 0.5N aqueous sodium hydroxide solution, once with 0.5N hydrochloric acid and then with water, thereafter dried and finally evaporated. The evaporation residue is recrystallized from an ethyl acetate-ligroin mixture to give 10.2 g. (60% of theory) ethyl 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxybenzoylamino)-ethyl]-phenoxy} -2-methylpropionate; m.p. 132°- 134° C.
A mixture of 11.3 g. (23.4 mMol) of this ethyl ester, 130 ml. methanol and 58.5 ml. (58.5 meq.) 1N aqueous potassium hydroxide solution is stirred for 2 hours at 40° C. 60 ml. 1N hydrochloric acid are then added dropwise thereto, solid material is filtered off with suction and the filter cake is washed with water, dried and recrystallized from an ethyl acetate-ligroin mixture. There are thus obtained 8.1 g. (76% of theory) 2-{ 4-[2-(3,5-di-tert.-butyl-4-hydroxy-benzoylamino)-ethyl]-phenoxy}-2-methylpropionic acid; m.p. 200°- 202° C.
The N-acetyl-tyramine used as starting material can be prepared by one of the two following methods:
1. 64.0 g. (0.466 mMol) tyramine are mixed, while stirring, with 200 ml. acetic anhydride, a clear solution thereby being formed, with spontaneous heating up. This solution is seeded with a few crystals of N-acetyl-tyramine, whereafter crystallization occurs immediately. The reaction mixture is rapidly cooled, filtered with suction, washed with diethyl ether and water and dried. There are obtained 59 g. (71% of theory) N-acetyl-tyramine with a melting point of 126° C. By evaporation of the mother liquor, dissolving the residue in dilute aqueous sodium hydroxide solution, filtration and acidification of the filtrate, there are obtained a further 5.5 g. (6% of theory) of N-acetyl-tyramine with a melting point of 122°- 124° C. After recrystallization from ethyl acetate, the N-acetyl-tyramine melts at 129°- 131° C.
2. To a solution of 54.9 g. (0.4 mol) tyramine in 200 ml. pyridine are added dropwise, while stirring at 30°- 35° C., 65.8 g. (0.84 mol) acetyl chloride. The reaction mixture is subsequently heated for 15 minutes on a boiling water-bath, then cooled and poured into an ice-water mixture. By the addition of concentrated hydrochloric acid, the mixture is rendered distinctly acidic and subsequently extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous calcium chloride and then evaporated. As residue, there are obtained 88.5 g. (quantitative yield) diacetyl-tyramine with melting point of 99°- 100° C., after recrystallization from benzene. The diacetyl-tyramine is now dissolved in 500 ml. methanol. 800 ml. (0.8 mol) 1N aqueous potassium hydroxide solution are then added dropwise, the temperature thereby increasing to about 30° C., and the reaction mixture subsequently maintained for 2 hours at an internal temperature of 50° C. The mixture is thereafter cooled, weakly acidified with concentrated hydrochloric acid and the methanol evaporated off in a vacuum. The product which crystallizes out is filtered off with suction, thoroughly washed with water and then dried. There are obtained 58.3 g. (81% of theory) N-acetyl-tyramine which, after recrystallization from ethyl acetate, melts at 131° C.
In a manner analogous to that described in Example 1, by the condensation of 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid with ethyl 2-[4-2-aminoethyl)-phenoxy]-2-methylpropionate in the presence of phosphorus trichloride, there is obtained, in a yield of 91% of theory, crude ethyl 2-{ 4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy } -2-methylpropionate in the form of a colorless oil and from this, by hydrolysis at 30° C., 2-{ 4-(2[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy } -2-methylpropionic acid in a yield of 55% of theory which, after recrystallization from an ethyl acetate-ligroin mixture, melts at 168°- 171° C.
The above-mentioned acid can also be prepared by the hydrolysis of the methyl ester which melts at 105°- 107° C., after recrystallization from ethyl acetate-ligroin. The methyl ester can be prepared, in a manner analogous to that described in Example 1, by the condensation of 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid with methyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate in the presence of phosphorus trichloride.
A mixture of 50 g. (0.18 mol) 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid, 24.6 g. (0.18 mol) tyramine and 150 ml. xylene is heated for 72 hours under a water separator at reflux temperature and subsequently evaporated in a vacuum. As residue, there are obtained 68.0 g. (95% of theory) N-[2-(4-hydroxyphenyl)-ethyl]-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)propionamide which, after recrystallization from ethyl acetate-ligroin, melts at 139°- 141° C.
68 g. (0.171 mol) of this amide are heated with 47.5 g. (0.342 mol) potassium carbonate in 2.5 liters butan-2-one for 2 hours at reflux temperature, then mixed with 50 g. (0.256 mol) ethyl 2-bromo-2-methylpropionate and 5 g. potassium iodide and again heated to reflux temperature. After 24 hours and 48 hours, there are again added 24.8 g. (0.128 mol) ethyl 2-bromo-2-methylpropionate and 23.7 g. (0.171 mol) potassium carbonate. After a total reaction period of 120 hours, the precipitate is filtered off with suction, washed with acetone and the combined filtrates evaporated. There are obtained 112 g. of an oily residue which still contains ethyl 2-bromo-2-methylpropionate. The oil is maintained for 5 hours at 70° C. under vacuum of 0.1 mm.Hg and then cooled. There is obtained a quantitative yield of crude ethyl 2 { 4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy } -2-methylpropionate in the form of a colorless oil.
In a manner analogous to that described in Example 1, from this ester there is obtained, by hydrolysis at 30° C., 2 -{ 4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy } -2-methylpropionic acid in a yield of 51% of theory. After recrystallization from ethyl acetate-ligroin, the compound has a melting point of 168°- 171° C.
In a manner analogous to that described in Example 1, by the reaction of ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate in the presence of phosphorus trichloride with the appropriate acids, there are obtained the following compounds:
(a) ethyl 2 -{ 4-[2-(3,5-di-tert.-butyl-4-hydroxyphenylacetamino)-ethyl]-phenoxy} -2-methylpropionate; m.p. 100°- 100.5° C., after recrystallization from diethyl ether; yield 67% of theory; and from this, by hydrolysis, 2 -{ 4-[2-(3,5-di-tert.-butyl-4-hydroxyphenylacetamino)-ethyl]-phenoxy{ -2-methylpropionic acid; m.p. of the sodium salt 214° C. (decomp.); yield 84% of theory.
(b) ethyl 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl-α-methylacetamino)-ethyl]-phenoxy}-2-methylpropionate; m.p. 118°- 120° C., after recrystallization from ethyl acetate-ligroin; yield 88% of theory; and from this, by hydrolysis, 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl-α-methylacetamino)-ethyl]-phenoxy}-2-methylpropionic acid; m.p. 80°- 83° C., after recrystallization from ethyl acetate/ligroin; yield 50% of theory.
(c) ethyl 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl-α,α-dimethylacetamino)-ethyl]-phenoxy}-2-methylpropionate; colorless, viscous oil; yield 41 % of theory; and from this, by hydrolysis, 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl-α,α-dimethylacetamino)-ethyl]-phenoxy}-2-methylpropionic acid.
(d) ethyl 2-{4-[2-{3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-acryloylamino}-ethyl]-phenoxy}-2-methylpropionate; m.p. 58°- 64° C. (solid foam); yield 88% of theory, and from this, by hydrolysis, 2-{4-[2-{3-(3,5-di-tert.-butyl-4-hydroxhphenyl)-acryloylamino}-ethyl]-phenoxy}-2-methylpropionic acid; m.p. 210.5°- 211° C., after recrystallization from acetone; yield 87% of theory.
(e) ethyl 2-{4-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylaminomethyl]-phenoxy}-2-methylpropionate; pure oil nD 20 = 1.5320; yield 72% of theory, and from this, by hydrolysis, 2-{4-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylaminomethyl]-phenoxy}-2-methylpropionic acid; m.p. 189° C., after recrystallization from methanol; yield 75% of theory.
In a manner analogous to that described in Example 1, by the reaction of 4-(2-aminoethyl)-phenoxyacetic acid in the presence of phosphorus trichloride with the appropriate acids, there are obtained the following compounds:
(a) ethyl 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxybenzoylamino)-ethyl]-phenoxy}-acetate; m.p. 129°- 129.5° C., after recrystallization from isopropanol; yield 70% of theory; and from this, by hydrolysis, 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxybenzoylamino)-ethyl]-phenoxy}-acetic acid; m.p. 209°- 210° C., after recrystallization from isopropanol/water; yield 55% of theory.
(b) ethyl 2-{4-[2-{3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino}-ethyl]-phenoxy}-acetate; colorless, very viscous oil nD 20 = 1.5390; yield 84% of theory; and from this, by hydrolysis, 2-{4-[2-{3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino}-ethyl]-phenoxy}-acetic acid; m.p. of the sodium salt 190° C. (decomp.); yield 75% of theory.
The ability of the instant compounds to lower the serum lipid level and the cholesterol level as well as their activity as thrombocyte aggregation inhibiting agents are demonstrated by the following illustrative experiments:
Experiment A
The test compounds were administered orally to male rats of a weight of about 200 g (10 animals per substance in each case) in the dosages listed below. The treatment continued for 7 days. On the seventh day the animals were killed by neck blow and bled white. The concentration of the triglycerides and the cholesterol in the serum of the animals was then determined enzymatically. The control animals were given carrier substances without test compound. The results, expressed as percent reduction as compared to the control animals, are set forth in the following Table:
TABLE __________________________________________________________________________ Prep. Dosage Reduction in % Test Compound Example No. in mg/kg Triglycerides Cholesterol __________________________________________________________________________ 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxy- 5 (a) 25 24 -- benzoylamino)-ethyl]-phenoxy}-acetic acid 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxy- 4 (b) 25 49 21 phenyl-α-methylacetamino)-ethyl]-phen- oxy}-2-methylpropionic acid 2-{4-[2-{3-(3,5-di-tert.-butyl-4- 4 (d) 50 13 -- hydroxyphenyl)-acryloylamino}-ethyl]- phenoxy}-2-methylpropionic acid 100 21 -- 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxy- 4 (a) 25 0 6 phenylacetamino)-ethyl]-phenoxy}-2- methylpropionic acid 2-{4-[3-(3,5-di-tert.-butyl-4-hydroxy- 4 (e) 25 27 3 phenyl)-propionylaminomethyl]-phenoxy}- 2-methylpropionic acid 2-{4-(2-[3-(3,5-di-tert.-butyl-4-hydroxy- 2 5 49 5 phenyl)-propionylamino]-ethyl)-phenoxy}- 2-methylpropionic acid 12.5 43 12 25 43 20 50 49 30 __________________________________________________________________________
Experiment B
In this experiment arachidonic acid was administered intravenously to male rabbits in a dosage of 1.4 mg/kg. One group of 5 rabbits was used as a control group and a second group was used as the test group. Two hours before injection of the arachidonic acid the test group was pre-treated with 2-{4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy}-2-methylpropionic acid in dosages of 10 mg/kg and 20 mg/kg.
Immediately after injection of the arachidonic acid in the stated dosage range, death of the control animals occurred, as described by Silver et al (Sci. 183, 1974, 1085). By pre-treatment of the test animals with the inventive compound a survival rate of 100% could be demonstrated even at the lower test dosage of 10 mg/kg.
The novel compounds may be administered by themselves or in conjunction with carriers which are pharmacologically acceptable, either active or inert. The dosage units are similar to those of the heretofore known anti-cholesterol agents, e.g., about 1 to 2 grams per day for an adult or about 30 mg/kg per day although higher or lower dosages can be used. Rather than a single dose it is preferable if the compounds are administered in the course of a day, i.e., about four applications of 500 mg. each at spaced time intervals or 8 of about 250 mg. each. A convenient form of administration is in a gelatin capsule.
For the preparation of pharmaceutical compositions, the new compounds according to the present invention are mixed in the usual manner with appropriate pharmaceutical diluents or carriers, arome, flavoring and coloring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example olive oil.
The new compounds according to the present invention can be administered orally or parenterally in admixture with solid or liquid pharmaceutical diluents or carriers. As injection medium, it is preferred to use water which contains the stabilizing agents, solubilizing agents and/or buffers conventionally used in injection solutions. Additives of this kind include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex-forming agents (such as ethylenediamine-tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbitan anhydrides.
Solid carrier materials include, for example, starch, lactose, mannitol, methyl, cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening agents.
It will be appreciated that the instant specification and examples are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.
Claims (18)
1. Phenoxyalkylcarboxylic acid compound of the formula: ##STR6## wherein B is a valency bond or a straight-chained or branched, saturated or unsaturated hydrocarbon radical containing up to 3 carbon atoms;
n is 1 or 2 and
R1, r2 and R3, which can be the same or different, are hydrogen atoms or lower alkyl; and the pharmacologically compatible salts thereof.
2. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein B is a valency bond.
3. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein B is a hydrocarbon radical of up to 3 carbon atoms.
4. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein B is alkylene of up to 3 carbon atoms.
5. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein B is alkenylene of up to 3 carbon atoms.
6. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein n is 1.
7. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein n is 2.
8. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein at least one of R1, R2 and R3 is hydrogen.
9. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 wherein at least one of R1, R2 and R3 is lower alkyl.
10. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 designated 2-{4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy}-2-methylpropionic acid.
11. Phenoxyalkylcarboxylic acid compound as claimed in claim 1 designated 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl-α-methylacetamino)-ethyl]-phenoxy}-2-methylpropionic acid.
12. Phenylalkylcarboxylic acid compound as claimed in claim 1 designated 2-{4-[2-{3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-acryloylamino}-ethyl]-phenoxy}-2-methylpropionic acid.
13. Phenylalkylcarboxylic acid compound as claimed in claim 1 designated 2-{4-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylaminomethyl]-phenoxy}-2-methylpropionic acid.
14. Phenylalkylcarboxylic acid compound as claimed in claim 1 designated 2-{4-[2-(3,5-di-tert.-butyl-4-hydroxybenzoylamino)-ethyl]-phenoxy}-acetic acid.
15. Therapeutic compositions for lowering the serum lipid and/or cholesterol level and for inhibiting thrombocyte aggregation in mammals comprising a pharmocologically acceptable carrier and, in therapeutically effective amounts, a phenoxyalkylcarboxylic acid compound as claimed in claim 1.
16. Method for lowering the serum lipid and/or cholesterol level and for inhibiting thrombocyte aggregation in mammals which method comprises administering thereto an effective amount of a phenoxyalkylcarboxylic acid compound as claimed in claim 1.
17. Method as claimed in claim 16 wherein said compound is applied at a dosage of about 30 mg/kg per day.
18. Method as claimed in claim 16 wherein said compound is at least one selected from the group consisting of:
2-{4-(2-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylamino]-ethyl)-phenoxy}-2-methylpropionic acid
2-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl-α-methylacetamino)-ethyl]-phenoxy}-2-methylpropionic acid
2-{4-[2-{3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-acryloylamino}-ethyl]-phenoxy}-2-methylpropionic acid
2-{4-[3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionylaminomethyl]-phenoxy}-2-methylpropionic acid
2-{4-[2-(3,5-di-tert.-butyl-4-hydroxybenzoylamino)-ethyl]-phenoxy}-acetic acid.
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DE2546996 | 1975-10-21 | ||
DE2546996A DE2546996C2 (en) | 1975-10-21 | 1975-10-21 | Phenoxyalkylcarboxylic acid derivatives, processes for producing the same and pharmaceuticals which contain these compounds as active ingredients |
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AU (1) | AU500761B2 (en) |
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DD (1) | DD126580A5 (en) |
DE (1) | DE2546996C2 (en) |
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FI (1) | FI762943A (en) |
FR (1) | FR2328461A1 (en) |
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HU (1) | HU175053B (en) |
IE (1) | IE43637B1 (en) |
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Cited By (10)
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US4318923A (en) * | 1980-04-10 | 1982-03-09 | Kaken Chemical Co., Ltd. | Benzaminoethylphenoxycyclohexylacetic acid derivatives |
US4710515A (en) * | 1987-03-17 | 1987-12-01 | Riker Laboratories, Inc. | Substituted biphenyl derivatives |
US4716178A (en) * | 1985-07-22 | 1987-12-29 | Riker Laboratories, Inc. | Substituted di-t-butylphenols |
AU602126B2 (en) * | 1985-07-22 | 1990-10-04 | Riker Laboratories, Inc. | Substituted di-t-butylphenols |
USRE33574E (en) * | 1987-03-17 | 1991-04-23 | Riker Laboratories, Inc. | Substituted biphenyl derivatives |
US5049572A (en) * | 1987-04-06 | 1991-09-17 | Riker Laboratories, Inc. | Substituted di-t-butylphenols and anti-allergic use thereof |
US5103037A (en) * | 1987-04-06 | 1992-04-07 | Riker Laboratories, Inc. | Substituted di-t-butylphenols |
US5122539A (en) * | 1990-02-12 | 1992-06-16 | Center For Innovative Technology | Allosteric hemoglobin modifiers useful for decreasing oxygen affinity and preserving oxygen carrying capability of stored blood |
US5248785A (en) * | 1990-02-12 | 1993-09-28 | Virginia Commonwealth University | Using allosteric hemoglobin modifiers to decrease oxygen affinity in blood |
US5705521A (en) * | 1990-02-12 | 1998-01-06 | The Center For Innovative Technology | Use of allosteric hemoglobin modifiers in combination with radiation therapy to treat carcinogenic tumors |
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US7129274B1 (en) | 1999-11-05 | 2006-10-31 | Emisphere Technologies Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
US7279597B1 (en) | 1999-11-05 | 2007-10-09 | Emisphere Technologies, Inc. | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
FR2898892A1 (en) * | 2006-03-24 | 2007-09-28 | Genfit Sa | New poly-substituted N-(phenethyl)benzamide derivatives are peroxisome proliferator activated receptor activators useful to treat e.g. type-2 diabetes, insulin-resistance, metabolic disorders, atherosclerosis and cardiovascular diseases |
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- 1975-10-21 DE DE2546996A patent/DE2546996C2/en not_active Expired
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- 1976-10-14 HU HU76BO1637A patent/HU175053B/en unknown
- 1976-10-14 AR AR265097A patent/AR211938A1/en active
- 1976-10-14 AU AU18701/76A patent/AU500761B2/en not_active Expired
- 1976-10-14 FI FI762943A patent/FI762943A/fi not_active Application Discontinuation
- 1976-10-14 CS CS766651A patent/CS188147B2/en unknown
- 1976-10-15 BE BE171557A patent/BE847347A/en unknown
- 1976-10-15 SU SU762413994A patent/SU656501A3/en active
- 1976-10-15 DD DD195295A patent/DD126580A5/xx unknown
- 1976-10-15 GB GB42900/76A patent/GB1502236A/en not_active Expired
- 1976-10-15 ZA ZA766183A patent/ZA766183B/en unknown
- 1976-10-15 NL NL7611409A patent/NL7611409A/en not_active Application Discontinuation
- 1976-10-18 CH CH1317476A patent/CH622497A5/de not_active IP Right Cessation
- 1976-10-18 PL PL1976193107A patent/PL103653B1/en unknown
- 1976-10-18 SE SE7611546A patent/SE7611546L/en not_active Application Discontinuation
- 1976-10-18 IT IT28457/76A patent/IT1070945B/en active
- 1976-10-18 US US05/733,542 patent/US4153728A/en not_active Expired - Lifetime
- 1976-10-19 AT AT776776A patent/AT345798B/en not_active IP Right Cessation
- 1976-10-19 LU LU76029A patent/LU76029A1/xx unknown
- 1976-10-19 DK DK470376A patent/DK470376A/en unknown
- 1976-10-20 FR FR7631507A patent/FR2328461A1/en active Granted
- 1976-10-20 ES ES452550A patent/ES452550A1/en not_active Expired
- 1976-10-20 IE IE2307/76A patent/IE43637B1/en unknown
- 1976-10-20 YU YU02559/76A patent/YU255976A/en unknown
- 1976-10-20 IL IL50736A patent/IL50736A/en unknown
- 1976-10-21 JP JP51126754A patent/JPS5268141A/en active Pending
- 1976-10-21 CA CA264,012A patent/CA1084523A/en not_active Expired
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US4716178A (en) * | 1985-07-22 | 1987-12-29 | Riker Laboratories, Inc. | Substituted di-t-butylphenols |
AU602126B2 (en) * | 1985-07-22 | 1990-10-04 | Riker Laboratories, Inc. | Substituted di-t-butylphenols |
US4710515A (en) * | 1987-03-17 | 1987-12-01 | Riker Laboratories, Inc. | Substituted biphenyl derivatives |
USRE33574E (en) * | 1987-03-17 | 1991-04-23 | Riker Laboratories, Inc. | Substituted biphenyl derivatives |
US5049572A (en) * | 1987-04-06 | 1991-09-17 | Riker Laboratories, Inc. | Substituted di-t-butylphenols and anti-allergic use thereof |
US5103037A (en) * | 1987-04-06 | 1992-04-07 | Riker Laboratories, Inc. | Substituted di-t-butylphenols |
US5122539A (en) * | 1990-02-12 | 1992-06-16 | Center For Innovative Technology | Allosteric hemoglobin modifiers useful for decreasing oxygen affinity and preserving oxygen carrying capability of stored blood |
US5248785A (en) * | 1990-02-12 | 1993-09-28 | Virginia Commonwealth University | Using allosteric hemoglobin modifiers to decrease oxygen affinity in blood |
US5705521A (en) * | 1990-02-12 | 1998-01-06 | The Center For Innovative Technology | Use of allosteric hemoglobin modifiers in combination with radiation therapy to treat carcinogenic tumors |
Also Published As
Publication number | Publication date |
---|---|
GB1502236A (en) | 1978-02-22 |
PL103653B1 (en) | 1979-07-31 |
FR2328461B1 (en) | 1978-11-17 |
AT345798B (en) | 1978-10-10 |
FI762943A (en) | 1977-04-22 |
LU76029A1 (en) | 1977-05-16 |
DE2546996C2 (en) | 1984-07-05 |
HU175053B (en) | 1980-05-28 |
ES452550A1 (en) | 1977-11-16 |
IL50736A (en) | 1980-01-31 |
IT1070945B (en) | 1985-04-02 |
DE2546996A1 (en) | 1977-04-28 |
YU255976A (en) | 1983-09-30 |
FR2328461A1 (en) | 1977-05-20 |
SU656501A3 (en) | 1979-04-05 |
CA1084523A (en) | 1980-08-26 |
DD126580A5 (en) | 1977-07-27 |
AR211938A1 (en) | 1978-04-14 |
DK470376A (en) | 1977-04-22 |
JPS5268141A (en) | 1977-06-06 |
CS188147B2 (en) | 1979-02-28 |
BE847347A (en) | 1977-04-15 |
ZA766183B (en) | 1977-10-26 |
NL7611409A (en) | 1977-04-25 |
IE43637L (en) | 1977-04-21 |
IL50736A0 (en) | 1976-12-31 |
AU1870176A (en) | 1978-04-20 |
IE43637B1 (en) | 1981-04-22 |
SE7611546L (en) | 1977-04-22 |
ATA776776A (en) | 1978-02-15 |
CH622497A5 (en) | 1981-04-15 |
AU500761B2 (en) | 1979-05-31 |
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